Anastasia L. Wise

A common MUC5B promoter polymorphism and pulmonary fibrosis.

BACKGROUND The mutations that have been implicated in pulmonary fibrosis account for only a small proportion of the population risk. METHODS Using a genomewide linkage scan, we detected linkage between idiopathic interstitial pneumonia and a 3.4-Mb region of chromosome 11p15 in 82 families. We then evaluated genetic variation in this region in gel-forming mucin genes expressed in the lung among 83 subjects with familial interstitial pneumonia, 492 subjects with idiopathic pulmonary fibrosis, and 322 controls. MUC5B expression was assessed in lung tissue. RESULTS Linkage and fine mapping were used to identify a region of interest on the p-terminus of chromosome 11 that included gel-forming mucin genes. The minor-allele of the single-nucleotide polymorphism (SNP) rs35705950, located 3 kb upstream of the MUC5B transcription start site, was present at a frequency of 34% among subjects with familial interstitial pneumonia, 38% among subjects with idiopathic pulmonary fibrosis, and 9% among controls (allelic association with familial interstitial pneumonia, P=1.2×10(-15); allelic association with idiopathic pulmonary fibrosis, P=2.5×10(-37)). The odds ratios for disease among subjects who were heterozygous and those who were homozygous for the minor allele of this SNP were 6.8 (95% confidence interval [CI], 3.9 to 12.0) and 20.8 (95% CI, 3.8 to 113.7), respectively, for familial interstitial pneumonia and 9.0 (95% CI, 6.2 to 13.1) and 21.8 (95% CI, 5.1 to 93.5), respectively, for idiopathic pulmonary fibrosis. MUC5B expression in the lung was 14.1 times as high in subjects who had idiopathic pulmonary fibrosis as in those who did not (P<0.001). The variant allele of rs35705950 was associated with up-regulation in MUC5B expression in the lung in unaffected subjects (expression was 37.4 times as high as in unaffected subjects homozygous for the wild-type allele, P<0.001). MUC5B protein was expressed in lesions of idiopathic pulmonary fibrosis. CONCLUSIONS A common polymorphism in the promoter of MUC5B is associated with familial interstitial pneumonia and idiopathic pulmonary fibrosis. Our findings suggest that dysregulated MUC5B expression in the lung may be involved in the pathogenesis of pulmonary fibrosis. (Funded by the National Heart, Lung, and Blood Institute and others.).

Detectable clonal mosaicism from birth to old age and its relationship to cancer

We detected clonal mosaicism for large chromosomal anomalies (duplications, deletions and uniparental disomy) using SNP microarray data from over 50,000 subjects recruited for genome-wide association studies. This detection method requires a relatively high frequency of cells with the same abnormal karyotype (>5–10%; presumably of clonal origin) in the presence of normal cells. The frequency of detectable clonal mosaicism in peripheral blood is low (<0.5%) from birth until 50 years of age, after which it rapidly rises to 2–3% in the elderly. Many of the mosaic anomalies are characteristic of those found in hematological cancers and identify common deleted regions with genes previously associated with these cancers. Although only 3% of subjects with detectable clonal mosaicism had any record of hematological cancer before DNA sampling, those without a previous diagnosis have an estimated tenfold higher risk of a subsequent hematological cancer (95% confidence interval = 6–18).

eXclusion: Toward Integrating the X Chromosome in Genome-wide Association Analyses

The X chromosome lags behind autosomal chromosomes in genome-wide association study (GWAS) findings. Indeed, the X chromosome is commonly excluded from GWAS analyses despite being assayed on all current GWAS microarray platforms. This raises the question: why are so few hits reported on the X chromosome? This commentary aims to examine this question through review of the current X chromosome results in the National Human Genome Research Institute Catalog of Published Genome-Wide Association Studies (NHGRI GWAS Catalog). It will also investigate commonly cited reasons for exclusion of the X chromosome from GWAS and review the tools currently available for X chromosome analysis. It will conclude with recommendations for incorporating X chromosome analyses in future studies.

The NIH Undiagnosed Diseases Program and Network: Applications to modern medicine.

INTRODUCTION The inability of some seriously and chronically ill individuals to receive a definitive diagnosis represents an unmet medical need. In 2008, the NIH Undiagnosed Diseases Program (UDP) was established to provide answers to patients with mysterious conditions that long eluded diagnosis and to advance medical knowledge. Patients admitted to the NIH UDP undergo a five-day hospitalization, facilitating highly collaborative clinical evaluations and a detailed, standardized documentation of the individuals phenotype. Bedside and bench investigations are tightly coupled. Genetic studies include commercially available testing, single nucleotide polymorphism microarray analysis, and family exomic sequencing studies. Selected gene variants are evaluated by collaborators using informatics, in vitro cell studies, and functional assays in model systems (fly, zebrafish, worm, or mouse). INSIGHTS FROM THE UDP In seven years, the UDP received 2954 complete applications and evaluated 863 individuals. Nine vignettes (two unpublished) illustrate the relevance of an undiagnosed diseases program to complex and common disorders, the coincidence of multiple rare single gene disorders in individual patients, newly recognized mechanisms of disease, and the application of precision medicine to patient care. CONCLUSIONS The UDP provides examples of the benefits expected to accrue with the recent launch of a national Undiagnosed Diseases Network (UDN). The UDN should accelerate rare disease diagnosis and new disease discovery, enhance the likelihood of diagnosing known diseases in patients with uncommon phenotypes, improve management strategies, and advance medical research.

The Undiagnosed Diseases Network of the National Institutes of Health A National Extension

In 2008, an Undiagnosed Diseases Program (UDP)1,2 was established within the Intramural Research Program of the National Institutes of Health (NIH). This program evaluates patients and families for whom medicine has failed to provide a diagnosis. Such patients have often spent years visiting medical centers and clinicians in different specialties across the country, accumulating large amounts of medical notes and test results, often at great emotional and financial cost. Indeed, patients who finally received a diagnosis through the UDP had spent 3 to 10 times more in physician consultation fees than consultations during their NIH evaluation (C. J. Tifft, written communication, 2015). The absence of a medical diagnosis creates a measure of concern, and perhaps suspicion, on the part of a patient’s family, friends, colleagues, and employer. Failure to establish a diagnosis can complicate and challenge the patient-physician relationship, which relies on the expectation that the cause of a disease can be identified and addressed. Yet for individuals with rare or novel disorders, the lack of a diagnosis occurs frequently. Of

Newborn Sequencing in Genomic Medicine and Public Health.

The rapid development of genomic sequencing technologies has decreased the cost of genetic analysis to the extent that it seems plausible that genome-scale sequencing could have widespread availability in pediatric care. Genomic sequencing provides a powerful diagnostic modality for patients who manifest symptoms of monogenic disease and an opportunity to detect health conditions before their development. However, many technical, clinical, ethical, and societal challenges should be addressed before such technology is widely deployed in pediatric practice. This article provides an overview of the Newborn Sequencing in Genomic Medicine and Public Health Consortium, which is investigating the application of genome-scale sequencing in newborns for both diagnosis and screening.

Cardiovascular Disease is Associated with COPD Severity and Reduced Functional Status and Quality of Life

Abstract Introduction: Smoking is a major risk factor for both cardiovascular disease (CVD) and chronic obstructive pulmonary disease (COPD). More individuals with COPD die from CVD than respiratory causes and the risk of developing CVD appears to be independent of smoking burden. Although CVD is a common comorbid condition within COPD, the nature of its relationships to COPD affection status and severity, and functional status is not well understood. Methods: The first 2,500 members of the COPDGene cohort were evaluated. Subjects were current and former smokers with a minimum 10 pack-year history of cigarette smoking. COPD was defined by spirometry as an FEV1/FVC < lower limit of normal (LLN) with further identification of severity by FEV1 percent of predicted (GOLD stages 2, 3, and 4) for the main analysis. The presence of physician-diagnosed self-reported CVD was determined from a medical history questionnaire administered by a trained staff member. Results: A total of 384 (15%) had pre-existing CVD. Self-reported CVD was independently related to COPD (Odds Ratio = 1.61, 95% CI = 1.18–2.20, p = 0.01) after adjustment for covariates with CHF having the greatest association with COPD. Within subjects with COPD, pre-existing self-reported CVD placed subjects at greater risk of hospitalization due to exacerbation, higher BODE index, and greater St. Georges questionnaire score. The presence of self-reported CVD was associated with a shorter six-minute walk distance in those with COPD (p < 0.05). Conclusions: Self-reported CVD was independently related to COPD with presence of both self-reported CVD and COPD associated with a markedly reduced functional status and reduced quality of life. Identification of CVD in those with COPD is an important consideration in determining functional status.

Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease

Background Many patients remain without a diagnosis despite extensive medical evaluation. The Undiagnosed Diseases Network (UDN) was established to apply a multidisciplinary model in the evaluation of the most challenging cases and to identify the biologic characteristics of newly discovered diseases. The UDN, which is funded by the National Institutes of Health, was formed in 2014 as a network of seven clinical sites, two sequencing cores, and a coordinating center. Later, a central biorepository, a metabolomics core, and a model organisms screening center were added. Methods We evaluated patients who were referred to the UDN over a period of 20 months. The patients were required to have an undiagnosed condition despite thorough evaluation by a health care provider. We determined the rate of diagnosis among patients who subsequently had a complete evaluation, and we observed the effect of diagnosis on medical care. Results A total of 1519 patients (53% female) were referred to the UDN, of whom 601 (40%) were accepted for evaluation. Of the accepted patients, 192 (32%) had previously undergone exome sequencing. Symptoms were neurologic in 40% of the applicants, musculoskeletal in 10%, immunologic in 7%, gastrointestinal in 7%, and rheumatologic in 6%. Of the 382 patients who had a complete evaluation, 132 received a diagnosis, yielding a rate of diagnosis of 35%. A total of 15 diagnoses (11%) were made by clinical review alone, and 98 (74%) were made by exome or genome sequencing. Of the diagnoses, 21% led to recommendations regarding changes in therapy, 37% led to changes in diagnostic testing, and 36% led to variant‐specific genetic counseling. We defined 31 new syndromes. Conclusions The UDN established a diagnosis in 132 of the 382 patients who had a complete evaluation, yielding a rate of diagnosis of 35%. (Funded by the National Institutes of Health Common Fund.)

Implementing the Single Institutional Review Board Model: Lessons from the Undiagnosed Diseases Network

In 2008, the National Institutes of Health (NIH) Undiagnosed Diseases Program (UDP)1,2 was established to provide answers for patients with conditions that had long eluded diagnosis. Based on the success of the UDP, the NIH elected to support the program’s expansion into a network of medical research centers in 2013, the Undiagnosed Diseases Network (UDN). Here we outline the steps required for implementing a single Institutional ReviewBoard (IRB), highlighting our experience in the UDN.

Host–Environment Interactions in Exposure-Related Diffuse Lung Diseases

Diffuse lung disease (DLD), also known as interstitial lung disease (ILD), comprises a group of relatively rare but devastating lung diseases that involve varying degrees of acute and chronic inflammation, and which may present with end-stage fibroproliferation. There are currently no proven therapeutic strategies to halt progression of DLDs. Thinking about DLDs has evolved over time from hypotheses invoking inflammation as the prime mover in the etiology of disease, to the current hypothesis that interactions between a damaged and frustrated epithelium, and the response of underlying mesenchymal cells that takes place, contribute to the fibroproliferative milieu. The greatest challenge to understanding the role of environmental exposures in pathogenesis of DLDs is that there is no clear consensus on the etiology and pathogenesis of these diseases. Emerging data on the relationship between loss of epithelial integrity and mesenchymal fibroproliferation support the hypothesis that the damage to the epithelium is a critical component in the development of DLDs that progress to a fibroproliferative presentation. Thus it follows that environmental stress which impacts the well-being of the epithelium may play a critical role in shifting the balance of lung homeostasis through ongoing insult as a result of exposure to environmental agents. Animal models that recapitulate the vulnerable epithelium observed in patients who develop fibrotic lung disease associated with DLDs will provide the best opportunity to understand mechanisms associated with the etiology of these diseases.